Method of preparing taxane derivatives

ABSTRACT

This invention relates to a method of preparing taxane derivatives of general formula (I) by esterification of protected baccatine III or 10-deacetylbaccatine III by means of an acid of general formula (VII), elimination of protection groupings of the ester obtained, and acylation of the amine function of the side chain. In formulae (I) and (VII): Ar stands for aryl, R is hydrogen or acetyl, R 1  is benzoyl or R 2  --CO--O-- in which R 2  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl, R 3  and R 4  may be the same or different and represent hydrogen, alkyl, alkenyl, aralkyl, aryl or alkoxy, and R 5  is an alkyl radical substituted by one or more chlorine atoms (2,2,2-trichloroethyl, (2-trichloromethylisopropyl). ##STR1##

DESCRIPTION OF THE INVENTION

The present invention relates to a new process for preparing taxanederivatives of general formula: ##STR2## which possess noteworthyantileukaemic and antitumour properties.

In the general formula (I):

R represents a hydrogen atom or an acetyl radical, R₁ represents abenzoyl radical or a radical R₂ --O--CO-- in which R₂ represents analkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenylor a nitrogenous heterocycle radical, and Ar represents an aryl radical.

More especially, R represents a hydrogen atom or an acetyl radical andR₁ represents a benzoyl radical or a radical R₂ --O--CO-- in which R₂represents:

an unbranched or branched alkyl radical containing 1 to 8 carbon atoms,an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radicalcontaining 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or abicycloalkyl radical containing 7 to 10 carbon atoms, these radicalsbeing optionally substituted with one or more substituents chosen fromhalogen atoms and hydroxyl radicals, alkyloxy radicals containing 1 to 4carbon atoms, dialkylamino radicals in which each alkyl portion contains1 to 4 carbon atoms, piperidino or morpholino radicals, 1-piperazinylradicals (optionally substituted at position 4 with an alkyl radicalcontaining 1 to 4 carbon atoms or with a phenylalkyl radical in whichthe alkyl portion contains 1 to 4 carbon atoms), cycloalkyl radicalscontaining 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6carbon atoms, phenyl, cyano or carboxyl radicals or alkyloxycarbonylradicals in which the alkyl portion contains 1 to 4 carbon atoms,

or a phenyl radical optionally substituted with one or more atoms orradicals chosen from alkyl radicals containing 1 to 4 carbon atoms oralkyloxy radicals containing 1 to 4 carbon atoms,

or a saturated or unsaturated 5- or 6-membered nitrogenous heterocyclicradical optionally substituted with one or more alkyl radicalscontaining 1 to 4 carbon atoms,

on the understanding that the cycloalkyl, cycloalkenyl or bicycloalkylradicals can be optionally substituted with one or more alkyl radicalscontaining 1 to 4 carbon atoms, and

Ar represents a phenyl or α- or β-naphthyl radical optionallysubstituted with one or more atoms or radicals chosen from halogen(fluorine, chlorine, bromine, iodine) atoms and alkyl, alkenyl, alkynyl,aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl,hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino,alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl,alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano and trifluoromethylradicals, on the understanding that the alkyl radicals and alkylportions of the other radicals contain 1 to 4 carbon atoms, and that thealkenyl and alkynyl radicals contain 3 to 8 carbon atoms and the arylradicals are phenyl or α- or β-naphthyl radicals.

Of very special importance are the products of general formula (I) inwhich R represents a hydrogen atom or an acetyl radical, R₁ represents abenzoyl or t-butoxycarbonylamino radical and Ar represents a phenylradical.

The products of general formula (I) in which R₁ represents a benzoylradical correspond to taxol and to 10-deacetyltaxol, and the products ofgeneral formula (I) in which R₁ represents a t-butoxycarbonyl radicalcorrespond to those which form the subject of European Patent 0,253,738.

According to the process which is described in International ApplicationPCT WO 92/09,589, the derivatives of general formula (I) may be obtainedby:

condensation of an oxazolidine derivative of general formula: ##STR3##in which Ar is defined as above, Boc represents a t-butoxycarbonylradical and R'₂ and R'₃, which may be identical or different, representan alkyl radical containing 1 to 4 carbon atoms optionally substitutedwith one or more aryl radicals, or an aryl radical, or alternatively R'₂and R'₃, together with the carbon atom to which they are linked, form a4- to 7-membered ring, with protected 10-deacetylbaccatin III orbaccatin III of general formula: ##STR4## in which G₁ represents a groupprotecting the hydroxyl function and G₂ represents an acetyl radical ora group protecting the hydroxyl function, to obtain a product of generalformula: ##STR5## in which Ar, R'₂, R'₃, G₁, G₂ and Boc are defined asabove,

treatment of the product of general formula (IV) in an acid medium underconditions which have no effect on G₁ and G₂, to obtain the product ofgeneral formula: ##STR6## in which Ar, G₁ and G₂ are defined as above,

treatment of the product of general formula (V) with a suitable reagentfor introducing a benzoyl radical or radical R₂ --O--CO--, to obtain aproduct of general formula: ##STR7## in which Ar, R₁, G₁ and G₂ aredefined as above, and

replacement of the protective groups G₁ and G₂ of the product of generalformula (VI) by hydrogen atoms to obtain the product of general formula(I).

It has now been found, and this forms the subject of the presentinvention, that the products of general formula (I) may be obtained:

1) by esterifying baccatin III or 10-deacetylbaccatin III of generalformula (III), in which G₁ and, where appropriate, G₂ represent a groupprotecting the hydroxyl function, preferably a trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl radical and stillmore especially a radical R₅ --O--CO-- in which R₅ is defined below, bymeans of an acid of general formula: ##STR8## in which Ar is defined asabove, R₃ and R₄, which may be identical or different, represent ahydrogen atom or an alkyl radical containing 1 to 4 carbon atoms or analkenyl radical containing 2 to 4 carbon atoms, or an aralkyl radical inwhich the alkyl portion contains 1 to 4 carbon atoms and the arylportion preferably represents a phenyl radical optionally substitutedwith one or more alkoxy radicals containing 1 to 4 carbon atoms, or anaryl radical preferably representing a phenyl radical optionallysubstituted with one or more alkoxy radicals containing 1 to 4 carbonatoms, or alternatively R₃ and R₄, together with the carbon atom towhich they are linked, form a 4- to 7-membered ring, and R₅ representsan alkyl radical containing 1 to 4 carbon atoms substituted with one ormore chlorine atoms, to obtain a product of general formula: ##STR9## inwhich Ar, R₃, R₄, R₅, G₁ and G₂ are defined as above,

2) by replacing the groups protecting the hydroxyl and amino functionsof the product obtained, of general formula (VIII), by hydrogen atoms toobtain the product of general formula: ##STR10## which Ar and R aredefined as above,

3) by treating the product obtained, of general formula (IX), with areagent which enables a substituent R₁ to be introduced on the aminofunction to obtain a product of general formula (I).

According to the present invention, the esterification of protected10-deacetylbaccatin III or baccatin III of general formula (III) bymeans of an acid of general formula (VII), in which R₅ represents a2,2,2-trichloroethyl or 2-(trichloromethyl)isopropyl radical, mayperformed in the presence of a condensing agent, for instance a diimidesuch as dicyclohexylcarbodiimide or a reactive carbonate such asdi-2-pyridyl carbonate, and an activating agent, for instance anaminopyridine such as 4-(dimethylamino) pyridine or4-pyrrolidinopyridine, working in an organic solvent chosen from etherssuch as tetrahydrofuran, diisopropyl ether, methyl t-butyl ether ordioxane, ketones such as methyl isobutyl ketone, esters such as ethylacetate, isopropyl acetate or n-butyl acetate, nitriles such asacetonitrile, aliphatic hydrocarbons such as pentane, hexane or heptane,halogenated aliphatic hydrocarbons such as dichloromethane or1,2-dichloroethane or aromatic hydrocarbons such as benzene, toluene,xylenes, ethylbenzene, isopropylbenzene or chlorobenzene, at atemperature of between -10° and 90° C. It is especially advantageous toperform the esterification working in an aromatic hydrocarbon at atemperature in the region of 20° C.

The esterification may also be carried out using the acid of generalformula (VII) in the form of an anhydride of general formula: ##STR11##in which Ar, R₃, R₄ and R₅ are defined as above, R₅ preferablyrepresenting a 2,2,2-trichloroethyl or 2-(trichloromethyl)isopropylradical, in the presence of an activating agent, for instance anaminopyridine such as 4-(dimethylamino)pyridine or4-pyrrolidinopyridine, working in an organic solvent chosen from etherssuch as tetrahydrofuran, diisopropyl ether, methyl t-butyl ether ordioxane, ketones such as methyl isobutyl ketone, esters such as ethylacetate, isopropyl acetate or n-butyl acetate, nitriles such asacetonitrile, aliphatic hydrocarbons such as pentane, hexane or heptane,halogenated hydrocarbons such as dichloromethane or 1,2-dichloroethaneor aromatic hydrocarbons such as benzene, toluene, xylenes,ethylbenzene, isopropylbenzene or chlorobenzene, at a temperature ofbetween 0° and 90° C.

The esterification may also be carried out using the acid of generalformula (VII) in the form of a halide or in the form of a mixedanhydride of general formula: ##STR12## in which Ar, R₃, R₄ and R₅ aredefined as above R₅ preferably representing a 2,2,2-trichloroethyl or2-(trichloromethyl)isopropyl radical, and X represents a halogen atom oran acyloxy or aroyloxy radical, optionally prepared in situ, in thepresence of a base which is preferably a nitrogenous organic base, forinstance a tertiary aliphatic amine such as triethylamine, pyridine, anaminopyridine such as 4-(dimethylamino)pyridine or4-pyrrolidinopyridine, working in an inert organic solvent chosen fromethers such as tetrahydrofuran, diisopropyl ether, methyl t-butyl etheror dioxane, ketones, esters such as ethyl acetate, isopropyl acetate orn-butyl acetate, nitriles such as acetonitrile, aliphatic hydrocarbonssuch as pentane, hexane or heptane, halogenated aliphatic hydrocarbonssuch as dichloromethane or 1,2-dichloroethane and aromatic hydrocarbonssuch as benzene, toluene, xylanes, ethylbenzene, isopropylbenzene orchlorobenzene, at a temperature of betwean 10° and 80° C., andpreferably in the region of 20° C.

It is preferable to use an activated derivative of general formula (XI)in which X represents a halogen atom or an acyloxy radical containing 1to 5 carbon atoms or an aroyloxy radical in which the aryl portion is aphenyl radical optionally substituted with 1 to 5 identical or differentatoms or radicals chosen from halogen (chlorine, bromine) atoms andnitro, methyl or methoxy radicals.

The replacement by hydrogen atoms of the groups protecting the hydroxyland amino functions of the product of general formula (VIII), in whichR₅ preferably represents a 2,2,2-trichloroethyl or2-(2-trichloromethylpropyl) radical and G₁ and, where appropriate, G₂represent a group protecting the hydroxyl function, preferably a2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonylradical, and is generally performed by treatment with zinc, optionallyin combination with copper, in the presence of acetic acid at atemperature of between 30° and 60° C., or by means of an inorganic ororganic acid such as hydrochloric acid or acetic acid dissolved in analiphatic alcohol containing 1 to 3 carbon atoms or in an aliphaticester such as ethyl acetate, isopropyl acetate or n-butyl acetate, inthe presence of zinc optionally in combination with copper.

The replacement by hydrogen atoms of the groups protecting hydroxyl andemino functions of the product of general formula (VIII), in which R₅preferably represents a 2,2,2-trichloroethyl or2-(2-trichloromethylpropyl) radical and G₁ and, where appropriate, G₂represent a group protecting the hydroxyl function, preferably atrialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triarylsilylradical, is generally performed by treatment in an acid medium such as,for example, hydrochloric acid dissolved in an aliphatic alcoholcontaining 1 to 3 carbon atoms (methanol, ethanol, propanol,isopropanol) or aqueous hydrofluoric acid at a temperature of between 0°and 40° C. to replace the protective groups G₁ and, where appropriate,G₂, and by treatment with zinc, optionally in combination with copper,in the presence of acetic acid at a temperature of between 30° and 60°C., or by means of an inorganic or organic acid such as hydrochloricacid or acetic acid dissolved in an aliphatic alcohol containing 1 to 3carbon atoms or an aliphatic ester such as ethyl acetate, isopropylacetate or n-butyl acetate, in the presence of zinc optionally incombination with copper, to replace R₅.

The replacement of the protective groups of the product of generalformula (VIII) hy hydrogen atoms may also be performed by electrolyticreduction.

The introduction of a substituent R₁ on the amino function of theproduct of general formula (IX) is performed by the action of benzoylchloride or a reactive derivative of general formula:

    R.sub.2 --O--CO--Y                                         (XII)

in which R₂ is defined as above and Y represents a halogen (fluorine,chlorine) atom or a residue --O--R₂ or --O--CO--OR₂, working in anorganic solvent, for instance an alcohol such as methanol, an aliphaticester such as ethyl acetate or a halogenated aliphatic hydrocarbon suchas dichloromethane, in the presence of an inorganic or organic base suchas sodium bicarbonate. In general, the reaction is performed at atemperature of between 0° and 50° C., and preferably in the region of20° C.

The acid of general formula (VII) may be obtained by saponification in abasic medium of the ester of general formula: ##STR13## in which Ar, R₃,R₄ and R₅ are defined as above and R₆ represents an alkyl radicalcontaining 1 to 4 carbon atoms optionally substituted with a phenylradical.

In general, the saponification is performed by means of an inorganicbase such as an alkali metal hydroxide (lithium, potassium, sodiumhydroxide) or an alkali metal carbonate or bicarbonate (sodiumbicarbonate, potassium carbonate or bicarbonate), in anaqueous-alcoholic medium such as a methanol/water mixture at atemperature of between 10° and 40° C., and preferably in the region of20° C.

The ester of general formula (XIII) may be obtained by the action of aproduct of general formula: ##STR14## in which R₃ and R₄ are defined asabove, optionally in the form of a dialkyl acetal or an enol alkylether, on a phenylisoserine derivative of general formula: ##STR15## inwhich Ar, R₅ and R₆ are defined as above, in racemic form or preferablyin the 2R,3S form, working in an inert organic solvent in the presenceof a strong inorganic acid such as sulphuric acid or strong organic acidsuch as p-toluenesulphonic acid, optionally in the form of a pyridiniumsalt, at a temperature between 0° C. and the boiling point of thereaction mixture. Solvents which are especially suitable are aromatichydrocarbons.

The product of general formula (XV) may be prepared under the conditionsdescribed in International Application PCT WO 92/09,589.

The anhydride of general formula (X) may be obtained by reacting adehydrating agent such as dicyclohexylcarbodiimide with the acid ofgeneral formula (VII), working in an organic solvent chosen fromhalogenated aliphatic hydrocarbons and aromatic hydrocarbons, at atemperature of between 0° and 30° C.

The activated acid of general formula (XI) may be obtained by the actionof a sulphuryl halide, preferably the chloride, or a product of generalformula:

    R.sub.5 --CO--Z                                            (XVI)

in which R₇ represents an alkyl radical containing 1 to 4 carbon atomsor a phenyl radical optionally substituted with 1 to 5 identical ordifferent atoms or radicals chosen from halogen atoms and nitro, methylor methoxy radicals and Z represents a halogen atom, preferably achlorine atom, on an acid of general formula (VII), working in asuitable organic solvent such as tetrahydrofuran in the presence of anorganic base, for instance a tertiary amine such as triethylamine, at atemperature of between 0° and 30° C.

EXAMPLES

The examples which follow illustrate the present invention.

EXAMPLE 1

9.48 cm³ of 2,2,2-trichloroethoxycarbonyl chloride are added in thecourse of 50 minutes at 0° C. to a solution of 11.7 g (60 mmol) ofmethyl (2R,3S)-phenylisoserinate and 5.22 g of pyridine in 180 cm³ ofmethylene chloride. The temperature of the reaction mixture is allowedto return to rise to a value in the region of 20° C. while the mixtureis stirred for 3 hours. The solution is washed with 100 cm³ of 0.1Naqueous hydrochloric acid solution and then with twice 50 cm³ of water.After drying of the organic phase and concentration thereof underreduced pressure, the residue is taken up with 300 cm³ of cyclohexane.The solvent is then partially concentrated under reduced pressure (60kPa) at 40° C. until the first crystals appear. The precipitate therebyobtained is isolated by filtration, then washed with cyclohexane anddried. 19.1 g of methyl(2R,3S)-2-hydroxy-3-phenyl-3-(2,2,2-trichloroethoxycarbonylamino)propionate,the characteristics of which are as follows, are thereby obtained in an86% yield:

proton NMR spectrum (360 MHz; DMSO-d₆ ; chemical shifts in ppm; couplingconstants J in Hz): 8.12 (d, J=9.2, 1H); 7.20 (M, 5H); 5.63 (M, 1H);4.89 (dd, J=5.1 and 9.2, 1H); 4.77 and 4.67 (AB syst, J=-12.3, 1H); 4.29(m, 1H); 3.46 (s, 3H).

151 mg of pyridinium para-toluenesulphonate are added to a solution of11.1 g (30 mmol) of methyl(2R,3S)-2-hydroxy-3-phenyl-3-(2,2,2-trichloroethoxycarbonylamino)propionateand 3.24 g of 2-methoxypropene in 100 cm³ of toluene. The reactionmixture is heated to boiling. 50 cm³ of a toluene solution containing19.5 g of 2-methoxypropene are added in the course of 2 hours.Distillation is performed until 80 cm³ of distillate are obtained. Thereaction mixture is cooled to a temperature in the region of 20° C.,treated with sodium bicarbonate and then washed with water. The organicsolution is dried and then concentrated under reduced pressure. 14.5 gof oily crude product are thereby obtained, which product ischromatographed on a silica column, eluting with a cyclohexane/ethylacetate mixture (90:10 by volume). 5.68 g of pure(4S,5R)-5-methoxycarbonyl-2,2-dimethyl-4-phenyl-3-(2,2,2-trichloroethoxycarbonyl)-1,3-oxazolidine(yield = 46%) and 4.95 g of pure(4S,5R)-5-methoxycarbonyl-2-methyl-2-isobutenyl-4-phenyl-3-(2,2,2-trichloroethoxycarbonyl)-11,3-oxazolidine(yield = 36.7%) are isolated.

EXAMPLE 2

A 6% (w/v) methanolic solution of potassium hydroxide is added to asolution of 1.24 g (3 mmol) of(4S,5R)-5-methoxycarbonyl-2,2-dimethyl-4-phenyl-3-(2,2,2-trichloroethoxycarbonyl)-1,3-oxazolidine.The reaction mixture is kept stirring for 4 hours at a temperature inthe region of 20° C. After the addition of 5 cm³ of water and stirringfor 30 minutes at a temperature in the region of 20° C., the reactionmixture is concentrated to dryness. The oily residue is taken up with 20cm³ of water and extracted with twice 20 cm³ of diisopropyl ether. Theaqueous phase is acidified by adding 1N aqueous hydrochloric acidsolution until the pH equals 2, and is then extracted with 20 cm³ ofmethylene chloride. The organic phase is dried and then concentratedunder reduced pressure. 1.15 g of(4S,5R)-5-carboxyl-2,2-dimethyl-4-phenyl-3-(2,2,2-trichloroethoxycarbonyl)-1,3-oxazolidineare thereby obtained in a 96% yield.

Similar results are obtained using(4S,5R)-5-methoxycarbonyl-2-methyl-2-isobutenyl-4-phenyl-3-(2,2,2-trichloroethoxycarbonyl)-11,3-oxazolidine.

EXAMPLE 3

0.495 g of dicyclohexylcarbodiimide is added at a temperature in theregion of 20° C. to a stirred solution of 0.95 g of(4S,5R)-5-carboxy-2,2-dimethyl-4-phenyl-3-(2,2,2-trichloroethoxycarbonyl)-1,3-oxazolidineand 1.43 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-13α-dihydroxy-9-oxo-7β,10β-bis(2,2,2-trichloroethoxycarbonyloxy)-11-taxeneand 0.039 g of 4-(dimethylamino)pyridine in 20 cm³ of anhydrous toluene.The reaction mixture is kept stirring for 2 hours. The dicyclohexylureais separated by filtration and then washed with toluene. The toluenephases are combined, washed successively with 0.1N aqueous hydroxhloricacid solution and saturated aqueous sodium bicarbonate solution, driedover sodium sulphate, filtered and then concentrated to dryness underreduced pressure. 2.15 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-7β,10.beta.-bis(2,2,2-trichloroethoxycarbonyloxy)-11-taxen-13α-yl(4S,5R)-3-(2,2,2-trichloroethoxycarbonyl)-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylateare thereby obtained in a yield in the region of 78%.

EXAMPLE 4

0.65 g of zinc powder is added to a stirred solution of 1.28 g of theproduct obtained in Example 3 in 5 cm³ of ethyl acetate, and 1.8 cm³ ofglacial acetic acid are then added dropwise in the course of 5 minutes.A slight exothermic reaction and an evolution of gas are noted. Thereaction mixture is then maintained at 45° C. for 90 minutes andthereafter cooled to a temperature in the region of 20° C. The zinc isseparated by filtration and then washed with ethyl acetate. The combinedorganic phases are concentrated to dryness under reduced pressure. Theresidue is taken up with toluene. The solution obtained is againconcentrated to dryness under reduced pressure. This operation isrepeated a first time with heptane and then with ethyl acetate. Theresidue is taken up with ethyl acetate. This solution is then extractedwith 10 cm³ of 0.1N aqueous hydrochloric acid solution. The aqueousphase is neutralized by adding 1N sodium hydroxide solution. 10 cm³ ofethyl acetate are added and the pH is then adjusted to 8 by addingsaturated aqueous sodium bicarbonate solution. After separation, theaqueous phase is extracted twice with 25 cm³ of ethyl acetate. Theorganic phases are combined, dried over sodium sulphate, filtered andthen concentrated to dryness under reduced pressure. 0.355 g of4-acetoxy-2α-benzoyloxy-5β-20-epoxy-1β,7α,10α-trihydroxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-amino-2-hydroxy-3-phenylpropionate is thereby obtained in a49% yield.

EXAMPLE 5

0.108 g of di-tert-butyl dicarbonate is added to a solution of 0.3 g ofthe product obtained in Example 4 in 5 cm³ of methanol. The reactionmixture is kept stirring for 15 hours at a temperature in the region of20° C. After the addition of 20 cm³ of water, the reaction mixture isextracted with 3 times 15 cm³ of methylene chloride. The aqueous phasesare combined, dried over sodium sulphate and then concentrated todryness under reduced pressure. 0.395 g of4-acetoxy-2α-benzoyloxy-5β-20-epoxy-1,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate isthereby obtained in a 70% yield.

Although the invention has been described in conjunction with specificembodiments, it is evident that many alternatives and variations will beapparent to those skilled in the art in light of the foregoingdescription. Accordingly, the invention is intended to embrace all ofthe alternatives and variations that fall within the spirit and scope ofthe appended claims. The above references are hereby incorporated byreference.

We claim:
 1. Process for preparing taxane derivatives of formula:##STR16## in which: R represents a hydrogen atom or an acetyl radical,and R₁ represents a benzoyl radical or a radical R₂ --O--CO-- in whichR₂ represents:an unbranched or branched alkyl radical containing 1 to 8carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, analkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radicalcontaining 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6carbon atoms or a bicycloalkyl radical containing 7 to 10 carbon atoms,these radicals being optionally substituted with at least onesubstituent selected from halogen atoms and hydroxyl radicals, alkyloxyradicals containing 1 to 4 carbon atoms, dialkylamino radicals in whicheach alkyl portion contains 1 to 4 carbon atoms, piperidino ormorpholino radicals, 1-piperazinyl radicals (optionally substituted atposition 4 with an alkyl radical containing 1 to 4 carbon atoms or witha phenylalkyl radical in which the alkyl portion contains 1 to 4 carbonatoms), cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenylradicals containing 4 to 6 carbon atoms, phenyl, cyano or carboxylradicals or alkyloxycarbonyl radicals in which the alkyl portioncontains 1 to 4 carbon atoms, or a phenyl radical optionally substitutedwith at least one atom or radical selected from alkyl radicalscontaining 1 to 4 carbon atoms or alkyloxy radicals containing 1 to 4carbon atoms, or a saturated or unsaturated 5- or 6-membered nitrogenousheterocyclic radical optionally substituted with at least one alkylradical containing 1 to 4 carbon atoms, the cycloalkyl, cycloalkenyl orbicycloalkyl radicals can be optionally substituted with at least onealkyl radical containing 1 to 4 carbon atoms, and Ar represents a phenylor α- or β-naphthyl radical optionally substituted with at least oneatom or radical selected from halogen including fluorine, chlorine,bromine, iodine atoms and alkyl, alkenyl, alkynyl, aryl, arylalkyl,alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto,formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino,alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl,dialkylcarbamoyl, cyano and trifluoromethyl radicals, the alkyl radicalsand alkyl portions of the other radicals contain 1 to 4 carbon atoms,and that the alkenyl and alkynyl radicals contain 3 to 8 carbon atomsand the aryl radicals are phenyl or α- or β-naphthyl radicals,comprising esterifying a protected 10-deacetylbaccatin III or baccatinIII derivative of formula: ##STR17## in which G₁ and, where appropriate,G₂ represent a group protecting the hydroxyl function, by means of anacid of formula: ##STR18## in which Ar is defined as above, R₃ and R₄,which may be identical or different, represent a hydrogen atom or analkyl radical containing 1 to 4 carbon atoms or an alkenyl radicalcontaining 2 to 4 carbon atoms, or an aralkyl radical in which the alkylportion contains 1 to 4 carbon atoms and the aryl portion represents aphenyl radical optionally substituted with at least one alkoxy radicalcontaining 1 to 4 carbon atoms, or an aryl radical representing a phenylradical optionally substituted with at least one alkoxy radicalcontaining 1 to 4 carbon atoms, or alternatively R₃ and R₄, togetherwith the carbon atom to which they are linked, form a 4- to 7-memberedring, and R₅ represents an alkyl radical containing 1 to 4 carbon atomssubstituted with at least one chlorine atom, or an activated derivativeof this acid, to obtain a product of formula: ##STR19## in which Ar, R₃,R₄, R₅, G₁ and G₂ are defined as above, b) replacing the groupsprotecting the hydroxyl and amino functions of the product obtained byhydrogen atoms to obtain a product of formula: ##STR20## in which Ar andR are defined as above, then c) treating the product thereby obtainedwith a reagent which enables a substituent R_(l) to be introduced on theamino function, and d) isolating the product obtained.
 2. Processaccording to claim 1, wherein the esterification is performed by meansof an acid of formula: ##STR21## in which Ar, R₃, R₄ and R₅ are definedas in claim 1, working in the presence of a condensing agent and anactivating agent in an organic solvent at a temperature of between -10°and 90° C.
 3. Process according to claim 2, wherein the condensing agentis selected from imides and reactive carbonates and the activating agentis selected from aminopyridines.
 4. Process according to claim 3,wherein the condensing agent is selected from dicyclohexylcarbodiimideand di-2-pyridyl carbonate and the activating agent is selected from4-(dimethylamino)pyridine and 4-pyrrolidinopyridine.
 5. Processaccording claim 2, wherein the solvent is selected from ethers, ketones,esters, nitriles, aliphatic hydrocarbons, halogenated aliphatichydrocarbons and aromatic hydrocarbons.
 6. Process according to claim 5,wherein the solvent is selected from aromatic hydrocarbons.
 7. Processaccording to claim 1, wherein the esterification is performed by meansof an anhydride of formula: ##STR22## in which Ar, R₃, R₄ and R₅ aredefined as in claim 1, working in the presence of an activating agent inan organic solvent at a temperature of between 0° and 90° C.
 8. Processaccording to claim 7, wherein the activating agent is selected fromaminopyridines.
 9. Process according to claim 8, wherein the activatingagent is chosen from 4-(dimethylamino)pyridine and4-pyrrolidinopyridine.
 10. Process according to claim 7, wherein thesolvent is selected from ethers, ketones, esters, nitriles, aliphatichydrocarbons, halogenated aliphatic hydrocarbons and aromatichydrocarbons.
 11. Process according to claim 1, wherein theesterification is performed by means of an activated acid of formula:##STR23## in which Ar, R₃, R₄ and R₅ are defined as above and Xrepresents a halogen atom or an acyloxy or aroyloxy radical, optionallyprepared in situ, in the presence of a base, working in an organicsolvent at a temperature of between 10° and 80° C.
 12. Process accordingto claim 11, wherein the base is selected from nitrogenous organicbases.
 13. Process according to claim 12, wherein the nitrogenousorganic base is selected from aliphatic tertiary amines, pyridine andaminopyridines.
 14. Process according to claim 11, wherein the organicsolvent is selected from ethers, ketones, esters, nitriles, aliphatichydrocarbons, halogenated aliphatic hydrocarbons and aromatichydrocarbons.
 15. Process according to claim 14, wherein the solvent isselected from aromatic hydrocarbons.
 16. Process according to claim 1,wherein the replacement by hydrogen atoms of the groups protecting thehydroxyl and amino functions is performed by treatment with zinc,optionally in combination with copper, in the presence of acetic acid ata temperature of between 30° and 60° C.
 17. Process according to claim1, wherein the replacement by hydrogen atoms of the groups protectingthe hydroxyl and amino function is performed by means of an inorganic ororganic acid dissolved in an aliphatic alcohol containing 1 to 3 carbonatoms or in an aliphatic ester, in the presence of zinc optionally incombination with copper.
 18. Process according to claim 16, wherein R₅represents a 2,2,2-trichloroethyl or 2-(2-trichloromethylpropyl) radicaland G₁ and, optionally, G₂ represent a 2,2,2-trichoroethoxycarbonyl or2-(2-trichloromethylpropoxy)carbonyl radical.
 19. Process accordingclaim 1, wherein the introduction of a substituent R₁ on the aminofunction is performed by the action of benzoyl chloride or a reactivederivative of general formula:

    R.sub.2 --O--CO--Y

in which Y represents a halogen atom and R₂ is defined as in claim 1,working in an organic solvent in the presence of an inorganic or organicbase at a temperature of between 0° and 50° C.
 20. Process according toclaim 19, wherein the solvent is selected from alcohols, aliphaticesters and halogenated aliphatic hydrocarbons.
 21. Process according toclaim 19, wherein the base is sodium bicarbonate.